Plasma Biomarkers Differentiate Parkinson's Disease From Atypical Parkinsonism Syndromes.

Objective: Parkinson's disease (PD) has significant clinical overlaps with atypical parkinsonism syndromes (APS), which have a poorer treatment response and a more aggressive course than PD. We aimed to identify plasma biomarkers to differentiate PD from APS. Methods: Plasma samples (n = 204) were obtained from healthy controls and from patients with PD, dementia with Lewy bodies (DLB), multiple system atrophy, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), or frontotemporal dementia (FTD) with parkinsonism (FTD-P) or without parkinsonism. We measured plasma levels of α-synuclein, total tau, p-Tau181, and amyloid beta 42 (Aß42) by immunomagnetic reduction-based immunoassay. Results: Plasma α-synuclein level was significantly increased in patients with PD and APS when compared with controls and FTD without parkinsonism (p < 0.01). Total tau and p-Tau181 were significantly increased in all disease groups compared to controls, especially in patients with FTD (p < 0.01). A multivariate and receiver operating characteristic curve analysis revealed that a cut-off value for Aß42 multiplied by p-Tau181 for discriminating patients with FTD from patients with PD and APS was 92.66 (pg/ml)2, with an area under the curve (AUC) of 0.932. An α-synuclein cut-off of 0.1977 pg/ml could separate FTD-P from FTD without parkinsonism (AUC 0.947). In patients with predominant parkinsonism, an α-synuclein cut-off of 1.388 pg/ml differentiated patients with PD from those with APS (AUC 0.87). Conclusion: Our results suggest that integrated plasma biomarkers improve the differential diagnosis of PD from APS (PSP, CBD, DLB, and FTD-P).

Eight-Channel AC Magnetosusceptometer of Magnetic Nanoparticles for High-Throughput and Ultra-High-Sensitivity Immunoassay.

An alternating-current magnetosusceptometer of antibody-functionalized magnetic nanoparticles (MNPs) was developed for immunomagnetic reduction (IMR). A high-sensitivity, high-critical-temperature superconducting quantum interference device was used in the magnetosusceptometer. Minute levels of biomarkers of early-stage neurodegeneration diseases were detectable in serum, but measuring each biomarker required approximately 4 h. Hence, an eight-channel platform was developed in this study to fit minimal screening requirements for Alzheimer's disease. Two consistent results were measured for three biomarkers, namely Aß40, Aß42, and tau protein, per human specimen. This paper presents the instrument configuration as well as critical characteristics, such as the low noise level variations among channels, a high signal-to-noise ratio, and the coefficient of variation for the biomarkers' IMR values. The instrument's ultrahigh sensitivity levels for the three biomarkers and the substantially shorter total measurement time in comparison with the previous single- and four-channels platforms were also demonstrated in this study. Thus, the eight-channel instrument may serve as a powerful tool for clinical high-throughput screening of Alzheimer's disease.

Detection of Plasma Biomarkers Using Immunomagnetic Reduction: A Promising Method for the Early Diagnosis of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common form of dementia. The development of assay technologies able to diagnose early-stage AD is important. Blood tests to detect biomarkers, such as amyloid and total Tau protein, are among the most promising diagnostic methods due to their low cost, low risk, and ease of operation. However, such biomarkers in blood occur at extremely low levels and are difficult to detect precisely. In the early 2000s, a highly sensitive assay technology, immunomagnetic reduction (IMR), was developed. IMR involves the use of antibody-functionalized magnetic nanoparticles dispersed in aqueous solution. The concentrations of detected molecules are converted to reductions in the ac magnetic susceptibility of this reagent due to the association between the magnetic nanoparticles and molecules. To achieve ultra-high sensitivity, a high-Tc superconducting-quantum-interference-device (SQUID) ac magnetosusceptometer was designed and applied to detect the tiny reduction in the ac magnetic susceptibility of the reagent. Currently, a 36-channeled high-Tc SQUID-based ac magnetosusceptometer is available. Using the reagent and this analyzer, extremely low concentrations of amyloid and total Tau protein in human plasma could be detected. Further, the feasibility of identifying subjects in early-stage AD via assaying plasma amyloid and total Tau protein is demonstrated. The results show a diagnostic accuracy for prodromal AD higher than 80% and reveal the possibility of screening for early-stage AD using SQUID-based IMR.

Plasma α-synuclein predicts cognitive decline in Parkinson's disease.

OBJECTIVE: α-Synuclein is critical to the pathogenesis of Parkinson's disease (PD). Few studies examined the plasma levels of α-synuclein due to the exceptionally low level of α-synuclein in plasma compared with cerebrospinal fluid. We aimed to investigate plasma α-synuclein in patients with PD of different disease severity. METHODS: There were total 114 participants, including 80 patients with PD and 34 controls, in the study. Participants received a complete evaluation of motor and non-motor symptoms, including cognitive function. We applied immunomagnetic reduction-based immunoassay to measure plasma levels of α-synuclein. RESULTS: Plasma levels of α-synuclein were significantly higher in patients with PD compared with controls (median: 1.56 pg/mL, 95% CI 1.02 to 1.98 pg/mL vs 0.02 pg/mL, 95% CI 0.01 to 0.03 pg/mL; p<0.0001). Although there was a significant increase in plasma α-synuclein levels in PD patients with a higher Hoehn-Yahr (H-Y) stage, there was no correlation with motor symptom severity, as assessed by Unified Parkinson's Disease Rating Scale part III scores, after confounders (age, gender, and disease duration) were taken into account. However, plasma α-synuclein levels were significantly higher in PD patients with dementia (PDD) than in PD patients with mild cognitive impairment (PD-MCI) or normal cognition (0.42 pg/mL, (95% CI 0.25 to 0.93) for PD with normal cognition; 1.29 pg/mL (95% CI 0.76 to 1.93) for PD-MCI and 4.09 pg/mL (95% CI 1.99 to 6.19) for PDD, p<0.01) and were negatively correlated with Mini-Mental State Examination scores (R2-adjusted=0.3004, p<0.001), even after confounder adjustment. CONCLUSIONS: Our data suggest that plasma α-synuclein level correlates with cognitive decline but not motor severity in patients with PD. Plasma α-synuclein could serve as a surrogate biomarker for patients at risk of cognitive decline.

Ultrasound-Induced Magnetic Imaging of Tumors Targeted by Biofunctional Magnetic Nanoparticles.

Biofunctional magnetic nanoparticles (MNPs) have been widely applied in biomedical engineering. MNPs are used as a contrast medium in magnetic imaging. Current methods of magnetic imaging, such as magnetic particle imaging and magnetic relaxometry, use small amounts of MNPs at target points far from the surface of the patient's body; these methods always consume considerable power to produce magnetic fields of high uniformity or gradient excitations. Some drawbacks, such as a limited imaging region, imaging system shielding, and complex algorithms based on assumptions of MNP properties or environmental factors, also limit the application of MNP methods in clinics. Therefore, this work proposes an interdisciplinary methodology of ultrasound-induced magnetic imaging that lacks these drawbacks. In the proposed imaging method, magnet sets were designed with uniform magnetic fields to magnetize MNPs. Besides, magnetized MNPs are subjected to ultrasound vibrations; the motion of the MNPs induces weak induction voltages at the imaging pickup coils. The highly sensitive scanning superconducting quantum interference device biosusceptometry with three sets of ultrasound focus chips was developed to construct magnetic tomography at three depths. A phantom test showed favorable consistency between the visual photos and the magnetic images of alpha-fetoprotein antibody (anti-AFP) MNP distribution on gauzes. In animal tests, rats with liver tumors were imaged at the pre-injection and post-injection of anti-AFP MNPs. The consistent results of magnetic images and ultrasound images implied that the proposed method has high clinical potential.

Plasma Tau Levels in Cognitively Normal Middle-Aged and Older Adults.

Using an ultra-sensitive technique, an immunomagnetic reduction assay, the plasma tau level can be measured to a limit of quantification of pg/ml. In total 126 cognitively normal middle-aged and older adults (45-95 years old) were recruited. The plasma tau levels were significantly higher in the older group (aged 65-95 years) 18.14 ± 7.33 pg/ml than those in the middle-aged group (aged 45-64 years) 14.35 ± 6.49 pg/ml when controlled gender and ApoEε4 carrier status (F = 3.102, P = 0.029). The ApoEε4 carriers had higher plasma tau levels than the non-carriers when controlled age and gender (F = 6.149, P = 0.001). Men had higher plasma tau levels than their women counterparts when controlled ApoEε4 carrier status and gender (F = 6.149, P = 0.001). The plasma tau levels were found to be positively associated with their ages (r = 0.359, P < 0.001). Regression analysis showed that age explained approximately 13% of the variance in the plasma tau levels, and explained more than 10% of the variance in the volumes of the hippocampus and white matter hypodensity (R2 change 0.123~0.167, all P < 0.001), and explained less than 10% of the variance in the volume of the amygdala, and central part of the corpus callosum (R2 change 0.085~0.097, all P = 0.001). However, the plasma tau levels do not further explain any residual variance in the volume of brain structures. In conclusion, the effect of age on the plasma tau levels should always be considered in clinical applications of this surrogate biomarker to middle-aged and elderly subjects.

Development of an ultra-high sensitive immunoassay with plasma biomarker for differentiating Parkinson disease dementia from Parkinson disease using antibody functionalized magnetic nanoparticles.

BACKGROUND: It is difficult to discriminate healthy subjects and patients with Parkinson disease (PD) or Parkinson disease dementia (PDD) by assaying plasma α-synuclein because the concentrations of circulating α-synuclein in the blood are almost the same as the low-detection limit using current immunoassays, such as enzyme-linked immunosorbent assay. In this work, an ultra-sensitive immunoassay utilizing immunomagnetic reduction (IMR) is developed. The reagent for IMR consists of magnetic nanoparticles functionalized with antibodies against α-synuclein and dispersed in pH-7.2 phosphate-buffered saline. A high-Tc superconducting-quantum-interference-device (SQUID) alternative-current magnetosusceptometer is used to measure the IMR signal of the reagent due to the association between magnetic nanoparticles and α-synuclein molecules. RESULTS: According to the experimental α-synuclein concentration dependent IMR signal, the low-detection limit is 0.3 fg/ml and the dynamic range is 310 pg/ml. The preliminary results show the plasma α-synuclein for PD patients distributes from 6 to 30 fg/ml. For PDD patients, the concentration of plasma α-synuclein varies from 0.1 to 100 pg/ml. Whereas the concentration of plasma α-synuclein for healthy subjects is significantly lower than that of PD patients. CONCLUSIONS: The ultra-sensitive IMR by utilizing antibody-functionalized magnetic nanoparticles and high-Tc SQUID magnetometer is promising as a method to assay plasma α-synuclein, which is a potential biomarker for discriminating patients with PD or PDD.

Rapid and quantitative discrimination of tumour cells on tissue slices.

After a needle biopsy, immunohistochemistry is generally used to stain tissue slices for clinically confirming tumours. Currently, tissue slices are immersed in a bioprobe-linked fluorescent reagent for several minutes, washed to remove the unbound reagent, and then observed using a fluorescence microscope. However, the observation must be performed by experienced pathologists, and producing a qualitative analysis is time consuming. Therefore, this study proposes a novel scanning superconducting quantum interference device biosusceptometry (SSB) method for avoiding these drawbacks. First, stain reagents were synthesised for the dual modalities of fluorescent and magnetic imaging by combining iron-oxide magnetic nanoparticles and the currently used fluorescent reagent. The reagent for the proposed approach was stained using the same procedure as that for the current fluorescent reagent, and tissue slices were rapidly imaged using the developed SSB for obtaining coregistered optical and magnetic images. Analysing the total intensity of magnetic spots in SSB images enables quantitatively determining the tumour cells of tissue slices. To confirm the magnetic imaging results, a traditional observation methodology entailing the use of a fluorescence microscope was also performed as the gold standard. This study determined high consistency between the fluorescent and magnetic spots in different regions of the tissue slices, demonstrating the feasibility of the proposed approach, which will benefit future clinical pathology.

Magnetic Clustering Effect during the Association of Biofunctionalized Magnetic Nanoparticles with Biomarkers.

We report herein an investigation into dynamic magnetic clustering that occurs during immunoassays as biofunctionalized magnetic nanoparticles (BMNs) become associated with biotargets. We measure the dynamic effective relaxation time τeff(t) and use scanning electron microscopy (SEM) and transmission electron microscopy (TEM) to investigate the C-reactive protein (CRP) as it associates with the BMN Fe3O4-antiCRP to form the magnetic cluster Fe3O4-antiCRP-CRP. The results indicate that τeff(t) increases with increasing association time. In addition, the ration Δτeff/τ0 as a function of CRP concentration follows a characteristic logistic function, which provides a basis for estimating the quantity of biomolecules with a detection sensitivity close to 0.1 ppm. After the association, SEM and TEM images show that CRP and Fe3O4-antiCRP conjugate to form Fe3O4-antiCRP-CRP clusters hundreds of nanometers in size. The SEM and TEM images provide direct evidence of the formation of magnetic clustering.

Using bio-functionalized magnetic nanoparticles and dynamic nuclear magnetic resonance to characterize the time-dependent spin-spin relaxation time for sensitive bio-detection.

In this work, we report the use of bio-functionalized magnetic nanoparticles (BMNs) and dynamic magnetic resonance (DMR) to characterize the time-dependent spin-spin relaxation time for sensitive bio-detection. The biomarkers are the human C-reactive protein (CRP) while the BMNs are the anti-CRP bound onto dextran-coated Fe3O4 particles labeled as Fe3O4-antiCRP. It was found the time-dependent spin-spin relaxation time, T2, of protons decreases as time evolves. Additionally, the ΔT2 of of protons in BMNs increases as the concentration of CRP increases. We attribute these to the formation of the magnetic clusters that deteriorate the field homogeneity of nearby protons. A sensitivity better than 0.1 µg/mL for assaying CRP is achieved, which is much higher than that required by the clinical criteria (0.5 mg/dL). The present MR-detection platform shows promise for further use in detecting tumors, viruses, and proteins.

Plasma Aß but not tau is related to brain PiB retention in early Alzheimer's disease.

Recent advances in biomarkers provide the possibility of early or preclinical diagnosis of Alzheimer's pathology. Currently, decreased levels of Aß-42 and increased levels of tau proteins in cerebral spinal fluid are considered reliable biomarkers of Alzheimer's disease (AD); however, little evidence exists for the use of amyloid and tau protein levels in the plasma as useful biomarkers. We investigated the potential use of plasma biomarkers to diagnose AD and explored their relationships with brain Aß deposition in amyloid imaging. We used an immunomagnetic reduction assay to measure the plasma levels of Aß40, Aß42, and tau proteins in 20 older control participants and 25 participants who had either mild cognitive impairment due to AD or early AD dementia. All participants received (11)C-labeled Pittsburgh compound B PET scans. The sensitivity of the plasma tau level at the cutoff value of 28.27 pg/mL was 92%, and the specificity was 100%; the sensitivity of the Aß42/40 ratio at the cutoff value of 0.3693 was 84%, and the specificity was 100%. Regression analyses of the effects of plasma protein levels on brain amyloid retention, as determined by standard uptake value ratios in either side of the frontal, parietal, and temporal lobes and the precuneus, are predicted only by ratios of plasma Aß42/40 (R(2) 0.326-0.449, all p < 0.001) but not by plasma tau levels. Plasma Aß in terms of Aß42/40 might provide an indirect estimation of Aß deposition in the brain.

Spatial repolarization heterogeneity detected by magnetocardiography correlates with cardiac iron overload and adverse cardiac events in beta-thalassemia major.

BACKGROUND: Patients with transfusion-dependent beta-thalassemia major (TM) are at risk for myocardial iron overload and cardiac complications. Spatial repolarization heterogeneity is known to be elevated in patients with certain cardiac diseases, but little is known in TM patients. The purpose of this study was to evaluate spatial repolarization heterogeneity in patients with TM, and to investigate the relationships between spatial repolarization heterogeneity, cardiac iron load, and adverse cardiac events. METHODS AND RESULTS: Fifty patients with TM and 55 control subjects received 64-channel magnetocardiography (MCG) to determine spatial repolarization heterogeneity, which was evaluated by a smoothness index of QTc (SI-QTc), a standard deviation of QTc (SD-QTc), and a QTc dispersion. Left ventricular function and myocardial T2* values were assessed by cardiac magnetic resonance. Patients with TM had significantly greater SI-QTc, SD-QTc, and QTc dispersion compared to the control subjects (all p values<0.001). Spatial repolarization heterogeneity was even more pronounced in patients with significant iron overload (T2*<20 ms, n = 20) compared to those with normal T2* (all p values<0.001). Loge cardiac T2* correlated with SI-QTc (r = -0.609, p<0.001), SD-QTc (r = -0.572, p<0.001), and QTc dispersion (r = -0.622, p<0.001), while all these indices had no relationship with measurements of the left ventricular geometry or function. At the time of study, 10 patients had either heart failure or arrhythmia. All 3 indices of repolarization heterogeneity were related to the presence of adverse cardiac events, with areas under the receiver operating characteristic curves (ranged between 0.79 and 0.86), similar to that of cardiac T2*. CONCLUSIONS: Multichannel MCG demonstrated that patients with TM had increased spatial repolarization heterogeneity, which is related to myocardial iron load and adverse cardiac events.

Plasma tau as a window to the brain-negative associations with brain volume and memory function in mild cognitive impairment and early Alzheimer's disease.

Neurofibrillary tangles are associated with cognitive dysfunction, and hippocampal atrophy with increased CSF tau markers. However, the plasma tau levels of Alzheimer's disease (AD) have not been well studied. We investigated plasma tau by using an immunomagnetic reduction assay in 20 patients with mild cognitive impairment (MCI) due to AD, 10 early AD dementia, and 30 healthy elders (HE). All received a 3D-brain MRI scan and a set of cognitive function test. We explored their relationships with both brain structure and cognitive functions. Images were analyzed to determine the brain volumes and gray matter densities. Patients with MCI or early AD had significantly increased plasma tau levels compared with HE. Plasma tau levels were negatively associated with the performance of logical memory, visual reproduction, and verbal fluency; also negatively associated with volume of total gray matter, hippocampus, amygdala; and gray matter densities of various regions. Regression analyses indicated that logical memory explained 0.394 and hippocampus volume predicted .608 of the variance of plasma tau levels, both P < 0.001. Education years were negatively associated with the gray matter densities of the supramarginal (r = -0.407), middle temporal gyrus (r = -0.40) and precuneus (r = -0.377; all P < 0.05) in HE; and negatively associated with plasma tau levels in patients (r = -0.626). We propose that plasma tau may serve as a window to both structure and function of the brain. Higher education is a protective factor against AD and is associated with lower plasma tau levels in patients.

QTc Heterogeneity in Rest Magnetocardiography is Sensitive to Detect Coronary Artery Disease: In Comparison with Stress Myocardial Perfusion Imaging.

BACKGROUND: Stress nuclear myocardial perfusion imaging (MPI) is an established method for diagnosis and prognosis of coronary artery disease (CAD). However, radiation exposure limits its clinical application. Magnetocardiography (MCG) has been proposed as a non-contact, rapid and non-radiation technique with high reproducibility. The aim of the study was to evaluate the diagnostic efficacy of rest MCG in CAD comparing to stress MPI. METHODS: We prospectively enrolled 55 patients with suspected CAD (64 ± 10 years) who were scheduled for coronary angiography (CA). MCG, stress (201)Tl MPI and CA were performed within 3 months. The spatial distribution maps of QTc interval (21 × 21 in resolution) were derived from a 64-channel MCG system (KRISS, Korea). T-wave propagation mapping, repolarization heterogeneity index with QTc dispersion and smoothness index of QTc (SI-QTc) were analyzed, and the diagnostic criteria for CAD were developed based on the receiver operating characteristic (ROC) curve analysis. RESULTS: Patients with significant CAD (≥ 70% luminal stenosis, n = 36) had higher QTc dispersion and SI-QTc than controls (both p < 0.05). The diagnostic sensitivity and specificity were 0.8330, 0.6842 for QTc dispersion ≥ 79 ms; 0.7778, 0.6842 for SI-QTc ≥ 9.1 ms; and 0.8611, 0.6842 for combination. There was no difference of area under ROC curve by using criteria of QTc dispersion ≥ 79 ms, SI-QTc ≥ 9.1 ms or combination (0.7588, 0.7310, 0.7727, p = NS), and non-inferior to stress MPI (p = NS). CONCLUSIONS: The QTc heterogeneity parameters of rest MCG yield a good sensitivity and acceptable specificity for detection of CAD, and may provide an alternative to stress MPI without stress and radiation. KEY WORDS: Coronary artery disease (CAD); Magnetocardiography (MCG); Myocardial perfusion imaging (MPI); Repolarization.

Combined plasma biomarkers for diagnosing mild cognition impairment and Alzheimer's disease.

A highly sensitive immunoassay, the immunomagnetic reduction, is used to measure several biomarkers for plasma that is related to Alzheimer's disease (AD). These biomarkers include Aß-40, Aß-42, and tau proteins. The samples are composed of four groups: healthy controls (n=66), mild cognitive impairment (MCI, n=22), very mild dementia (n=23), and mild-to-serve dementia, all due to AD (n=22). It is found that the concentrations of both Aß-42 and tau protein for the healthy controls are significantly lower than those of all of the other groups. The sensitivity and the specificity of plasma Aß-42 and tau protein in differentiating MCI from AD are all around 0.9 (0.88-0.97). However, neither plasma Aß-42 nor tau-protein concentration is an adequate parameter to distinguish MCI from AD. A parameter is proposed, which is the product of plasma Aß-42 and tau-protein levels, to differentiate MCI from AD. The sensitivity and specificity are found to be 0.80 and 0.82, respectively. It is concluded that the use of combined plasma biomarkers not only allows the differentiation of the healthy controls and patients with AD in both the prodromal phase and the dementia phase, but it also allows AD in the prodromal phase to be distinguished from that in the dementia phase.

Anti-CEA-functionalized superparamagnetic iron oxide nanoparticles for examining colorectal tumors in vivo.

Although the biomarker carcinoembryonic antigen (CEA) is expressed in colorectal tumors, the utility of an anti-CEA-functionalized image medium is powerful for in vivo positioning of colorectal tumors. With a risk of superparamagnetic iron oxide nanoparticles (SPIONPs) that is lower for animals than other material carriers, anti-CEA-functionalized SPIONPs were synthesized in this study for labeling colorectal tumors by conducting different preoperatively and intraoperatively in vivo examinations. In magnetic resonance imaging (MRI), the image variation of colorectal tumors reached the maximum at approximately 24 h. However, because MRI requires a nonmetal environment, it was limited to preoperative imaging. With the potentiality of in vivo screening and intraoperative positioning during surgery, the scanning superconducting-quantum-interference-device biosusceptometry (SSB) was adopted, showing the favorable agreement of time-varied intensity with MRI. Furthermore, biological methodologies of different tissue staining methods and inductively coupled plasma (ICP) yielded consistent results, proving that the obtained in vivo results occurred because of targeted anti-CEA SPIONPs. This indicates that developed anti-CEA SPIONPs owe the utilities as an image medium of these in vivo methodologies.

Usefulness of magnetocardiography to detect coronary artery disease and cardiac allograft vasculopathy.

BACKGROUND: Electrophysiological information as well as anatomic information are important for the detection of coronary artery lesions. The aim of this study was to assess the efficacy of resting magnetocardiography (MCG) in stable coronary artery disease (CAD) and cardiac allograft vasculopathy (CAV). METHODS AND RESULTS: MCG and coronary angiography were performed within 1 month in 75 patients with suspected CAD and in 26 subjects after orthotopic heart transplantation (OHT). Plaque volumes were additionally measured on intravascular ultrasound in OHT recipients. The spatially distributed QT(c) interval maps were constructed with 64-channel MCG. A T-wave propagation map and QT(c) heterogeneity index including QT(c) dispersion and smoothness index of QT(c) (SI-QT(c)) were derived for ischemia detection and localization. CAD patients had higher QT(c) dispersion and SI-QT(c). Receiver operating characteristic curve analysis identified SI-QT(c) ≥9 ms, QT(c) dispersion ≥79 ms as the optimal cut-off for detecting CAD (diagnostic accuracy, 0.7953, 0.7819), better than T-wave propagation (0.6594, P<0.05). There was no significant difference of QT(c) dispersion between CAD and OHT subjects. In OHT recipients, QT(c) dispersion positively correlated with plaque volume, and SI-QT(c) progressively increased after transplantation. Using T-wave propagation mapping, regionally increased dispersion could be demonstrated in CAD patients, but increased dispersion was noted in fewer OHT recipients. CONCLUSIONS: MCG is clinically feasible as a non-invasive tool for diagnosis of CAD, and could be used as a surrogate marker of CAV.

A noninvasive method to determine the fate of Fe(3)O(4) nanoparticles following intravenous injection using scanning SQUID biosusceptometry.

Magnetic nanoparticles (MNPs) of Fe(3)O(4) have been widely applied in many medical fields, but few studies have clearly shown the outcome of particles following intravenous injection. We performed a magnetic examination using scanning SQUID biosusceptometry (SSB). Based on the results of SSB analysis and those of established in vitro nonmagnetic bioassays, this study proposes a model of MNP metabolism consisting of an acute metabolic phase with an 8 h duration that is followed by a chronic metabolic phase that continues for 28 d following MNP injection. The major features included the delivery of the MNPs to the heart and other organs, the biodegradation of the MNPs in organs rich with macrophages, the excretion of iron metabolites in the urine, and the recovery of the iron load from the liver and the spleen. Increases in serum iron levels following MNP injection were accompanied by increases in the level of transferrin in the serum and the number of circulating red blood cells. Correlations between the in vivo and in vitro test results indicate the feasibility of using SSB examination for the measurement of MNP concentrations, implying future clinical applications of SSB for monitoring the hematological effects of MNP injection.

Discriminating hepatocellular carcinoma in rats using a high-Tc SQUID detected nuclear resonance spectrometer in a magnetic shielding box.

In this study, we report the spin-lattice relaxation rate of hepatocellular carcinoma (HCC) and normal liver tissue in rats using a high-T(c) superconducting quantum interference device (SQUID) based nuclear magnetic resonance (NMR) spectrometer. The resonance spectrometer used for discriminating liver tumors in rats via the difference in longitudinal relaxation time in low magnetic fields was set up in a compact and portable magnetic shielding box. The frequency-domain NMR signals of HCC tissues and normal liver tissues were analyzed to study their respective longitudinal relaxation rate T(1) (-1). The T(1) (-1) of liver tissues for ten normal rats and ten cancerous rats were investigated respectively. The averaged T(1) (-1) value of normal liver tissue was (6.41±0.66) s(-1), and the averaged T(1) (-1) value of cancerous tissue was (3.38±0.15) s(-1). The ratio of T(1) (-1) for normal liver tissues and cancerous liver tissues of the rats investigated is estimated to be 1.9. Since this significant statistical difference, the T(1) (-1) value can be used to distinguish the HCC tissues from normal liver tissues. This method of examining liver and tumor tissues has the advantages of being convenient, easy to operate, and stable.

In vivo screening of hepatocellular carcinoma using AC susceptibility of anti-alpha fetoprotein-activated magnetic nanoparticles.

With antibody-mediated magnetic nanoparticles (MNPs) applied in cancer examinations, patients must pay at least twice for MNP reagents in immunomagnetic reduction (IMR) of in vitro screening and magnetic resonance imaging (MRI) of in vivo tests. This is because the high maintenance costs and complex analysis of MRI have limited the possibility of in vivo screening. Therefore, this study proposes novel methods for in vivo screening of tumors by examining the AC susceptibility of bound MNPs using scanning superconducting-quantum-interference-device (SQUID) biosusceptometry (SSB), thereby demonstrating high portability and improved economy. The favorable agreement between in vivo tests using SSB and MRI demonstrated the feasibility of in vivo screening using SSB for hepatocellular carcinoma (HCC) targeted by anti-alpha fetoprotein (AFP)-mediated MNPs. The magnetic labeling was also proved by in vitro tests using SSB and biopsy assays. Therefore, patients receiving bioprobe-mediated MNPs only once can undergo in vivo screening using SSB in the future.